This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Project 4: PI [unreadable]Surojit Paul SUBPROJECT DESCRIPTION In our initial project we proposed to test the hypothesis that STEP, a striatal enriched tyrosine phosphatase plays a critical role in neuronal cell death by regulating the temporal activity of p38 and ERK MAP kinase signaling pathway. During the previous funding periods we have demonstrated that p38 MAP kinase is a substrate of STEP. Bio-chemical and immunocytochemical experiments in cell lines showed that active STEP can block stress (sorbitol) induced tyrosine phosphorylation and nuclear translocation of p38 MAP kinase. Studies in primary neuronal cultures further established that transient stimulation glutamate/NMDA receptor leads to activation and nuclear translocation of p38 MAP kinase. Whereas a more sustained stimulation of glutamate/NMDA receptor leads to activation of STEP, which limits the duration of p38 activity as well as its translocation to the nucleus.